| Background:Breast cancer is the most common malignant tumor among women in the world,which seriously endangers the safety and physical and mental health of women.The incidence of female breast cancer in China is increasing year by year,with a larger increase.Breast cancer is highly heterogeneous,even in patients with the same histological type of breast cancer,the response to treatment and prognosis are different.In addition,at the molecular level,breast cancer has different subtypes and immunogenicity.The molecular and immunological characteristics of breast cancer indicate that there is a close relationship between the tumor tissue and the surrounding immune components and their regulatory factors.That is,tumor microenvironment plays a key role in the occurrence and development of breast cancer.Immune escape is an important part of cancer immuno-editing.PD-1/PD-L1 is an important negative costimulatory molecule which can regulate T cells,which is closely related to mediating immune escape of tumors and is an important target for anti-cancer therapy.On the other hand,the expression of PD-L1 on tumor cells and PD-1 on T cells plays an important role in predicting curative effect and evaluating prognosis in microenvironment of many kinds of tumors,including breast cancer.In addition,Treg cells can play a negative role in immune regulation through a variety of mechanisms,and FoxP3 is the most specific marker of Treg cells.FoxP3~+Treg cells can mediate immune escape of tumor cells through killing T cells directly,competitive binding cytokines and secreting inhibitory cytokines.CD8~+T cells are the main effector cells of anti-tumor immunity and the most important subtypes of TIL,which play a key role in the immune clearance.The level of CD8~+T cells in tumor microenvironment is closely related to the curative effect and prognosis of patients.Chemotherapy can inhibit and kill cancer cells through different mechanisms,and it is an important treatment for breast cancer.However,chemotherapeutic drugs not only affect tumor cells,but also have different effects on immune components in tumor microenvironment,which lead to microenvironmental remodeling,and then affect the therapeutic effect and prognosis of patients.By comparing the changes of some immune parameters in tumor microenvironment of breast cancer before and after neoadjuvant chemotherapy,it is of great significance to explore the relationship between tumor microenvironment and clinicopathological characteristics,curative effect and prognosis.Objective:The purpose of this study was to detect the percentage of PD-L1,PD-1,CD8 and FoxP3 in tumor microenvironment of breast cancer before and after neoadjuvant chemotherapy,and to analyze its correlation with clinicopathological features,curative effect of neoadjuvant chemotherapy and prognosis of patients.Methods:The paraffin sections from biopsy and postoperative tissue samples of 54 breast cancer patients with complete clinical data were collected in this study from May2012 to October 2017 in the First Hospital of Jilin University.Multiple fluorescence immunohistochemistry was used to detect the expression of PD-L1,PD-1,CD8 and FoxP3 in tumor microenvironment of 54 patients with breast cancer before and after neoadjuvant chemotherapy.Combined with the clinical and pathological data of the patients,the correlation between the changes and the clinical features,efficacy of neoadjuvant chemotherapy and prognosis was analyzed by SPSS 21.0 software.Results:1.Clinicopathological characteristics of patients with breast cancer:the median age of onset in 54 female breast cancer patients was 49.5 years old(27~66 years old);there were 33 patients with stage II and 21 patients with stage III before operation;among the molecular typing of breast cancer,25 cases(46%)were Luminal breast cancer,20 cases(37%)were HER-2 positive breast cancer,9 cases(17%)were triple negative breast cancer;with regard to the treatment regimen,9 patients(17%)received both neoadjuvant chemotherapy and neoadjuvant molecular targeted therapy,while the rest(83%)received only neoadjuvant chemotherapy;pCR was achieved in 7patients(13%)after neoadjuvant chemotherapy.2.Changes of some immune parameters in tumor microenvironment before and after neoadjuvant chemotherapy in patients with breast cancer:the percentage of PD-L1 positive cells is on the rise after neoadjuvant chemotherapy and the difference was not statistically significant(P=0.118);there was no significant change in the percentage of PD-1 positive cells;the percentage of CD8 positive cells decreased,the difference was statistically significant(P<0.001);the percentage of FoxP3 positive cells showed a downward trend,and the difference was not statistically significant(P=0.359).There was a correlation between the percentage of positive cells in PD-L1 and PD-1 before and after neoadjuvant chemotherapy(P=0.014,P=0.007).3.Correlation between some immune parameters in tumor microenvironment and Miller-Payne grading of patients with breast cancer:the percentage of CD8 positive cells in tumor microenvironment before neoadjuvant chemotherapy was correlated with Miller-Payne grading(P=0.036)and the higher the percentage of CD8 positive cells,the higher the Miller-Payne grading;the percentage of CD8 positive cells before neoadjuvant chemotherapy was an factor affecting Miller-Payne grading(P=0.043,HR=5.753).4.Correlation between clinicopathological features and prognosis in patients with breast cancer:before neoadjuvant chemotherapy,HER-2 status and Miller-Payne grading were correlated with DFS(P=0.042,P=0.017)and DFS was better in patients with HER-2 negative or Miller-Payne grading 4~5;HER-2 status is an independent risk factor for DFS(P=0.004),and tumor size is an independent risk factor for OS(P=0.045).5.Correlation between some immune parameters in tumor microenvironment and prognosis of patients with breast cancer:the percentage of CD8 positive cells in tumor microenvironment after neoadjuvant chemotherapy was related to DFS(P=0.030),and the higher the percentage of CD8 positive cells,the better DFS;the percentage of FoxP3 positive cells in tumor microenvironment before neoadjuvant chemotherapy is an independent risk factor for DFS(P=0.048)and the higher the percentage of FoxP3positive cells,the worse the DFS.6.Correlation between some immune parameters in tumor microenvironment and prognosis of patients with different molecular types of breast cancer:in patients with Luminal breast cancer,the percentage of PD-L1 positive cells was correlated with DFS before neoadjuvant chemotherapy(P=0.024)and the lower the percentage of PD-L1 positive cells,the better the DFS.Conclusion:1.After neoadjuvant chemotherapy,the percentage of CD8 positive cells in tumor microenvironment of breast cancer decreased,while the percentage of PD-L1 positive cells is on the rise,the percentage of PD-1 positive cells did not change significantly,the percentage of FoxP3 positive cells showed a downward trend,but the difference was not statistically significant.This suggests that neoadjuvant chemotherapy can regulate the microenvironment of breast cancer,affect the expression of some immune components and change the immune state of the body.2.There was a positive correlation between the percentage of PD-1 positive cells and PD-L1 positive cells in tumor microenvironment of breast cancer before and after neoadjuvant chemotherapy,which confirmed that there was a correlation between PD-1 and PD-L1 in tumor microenvironment of breast cancer.3.The percentage of CD8 positive cells in tumor microenvironment of breast cancer before neoadjuvant chemotherapy was related to Miller-Payne grading,and it was an influencing factor of Miller-Payne grading.The higher the percentage of CD8positive cells,the higher the Miller-Payne grading.This suggests that the infiltration level of CD8~+TIL in tumor microenvironment of breast cancer before neoadjuvant chemotherapy may predict the curative effect.4.The percentage of CD8 positive cells in tumor microenvironment of breast cancer after neoadjuvant chemotherapy is correlated with DFS.The DFS of patients with high percentage of CD8 positive cells was better than that of patients with low percentage of CD8 positive cells.The percentage of FoxP3 positive cells in breast cancer microenvironment before neoadjuvant chemotherapy is an independent risk factor for DFS.For patients with Luminal breast cancer,the percentage of PD-L1positive cells before neoadjuvant chemotherapy was correlated with DFS.The DFS of patients with low percentage of PD-L1 positive cells was better than that of patients with high percentage of PD-L1 positive cells.In addition,the tumor size was related to DFS and OS.The smaller the diameter of the tumor before neoadjuvant chemotherapy,the better the DFS and OS.Miller-Payne grading is related to DFS.The higher the Miller-Payne grading,the better the DFS.HER-2 status is an independent risk factor for DFS,and tumor size is an independent risk factor for OS.This suggests that the expression of FoxP3 before neoadjuvant chemotherapy and the percentage of CD8 positive cells after neoadjuvant chemotherapy in tumor microenvironment can predict prognosis.Tumor size,HER-2 status before neoadjuvant chemotherapy and Miller-Payne grading after neoadjuvant chemotherapy may play an important role in predicting prognosis. |
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